This document discusses Dent's disease, a rare inherited kidney disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and chronic kidney disease. It provides details on the genetics, pathophysiology, diagnosis, and treatment of the two main types - Dent's disease type 1 caused by mutations in the CLCN5 gene, and type 2 caused by mutations in the OCRL1 gene. The document reviews the characteristic features and clinical presentation of each type, as well as supportive treatments aimed at preventing kidney stone formation and slowing kidney function decline. Prognosis is outlined, with affected males having a high risk of end stage renal disease by the 3rd to 5th decade
Thrombotic Microangiopathies are diverse group of disorders wherein thrombocytopenia, hemolytic anemia and organ dysfunction such as Kidney and brain occur . Major recent advances in this field have occurred which opens up oppurtunities to effectively manage its clinical challenges .
Thrombotic Microangiopathies are diverse group of disorders wherein thrombocytopenia, hemolytic anemia and organ dysfunction such as Kidney and brain occur . Major recent advances in this field have occurred which opens up oppurtunities to effectively manage its clinical challenges .
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Thrombotic Microangiopathy (TMA) in Adults and Acute Kidney Injury - Dr. GawadNephroTube - Dr.Gawad
- English version of this lecture is available at:
https://youtu.be/zrFm0hAZk2A
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- Recorded videos of this lecture:
English Language version of this lecture is available at:
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Thrombotic Microangiopathy (TMA) in Adults and Acute Kidney Injury - Dr. GawadNephroTube - Dr.Gawad
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The Many Faces of Hyperparathyroidism & Advances in TreatmentBabak Larian
Hyperparathyroidism is a rare disease that affects the whole body and can cause potentially debilitating symptoms. Unfortunately, parathyroid disease is often poorly understood, even by parathyroid specialists. Because the signs and symptoms of hyperparathryoidism are similar to other conditions (including aging, stress, depression, menopause, fibromyalgia, etc.), patients are often misdiagnosed. As such, it is Dr Larian's goal to educate both physicians and patients more on the different manifestations of the disease and treatment so that patients can receive the care they deserve.
This presentation - The Many Faces of Hyperparathyroidism & Advances in Treatment - has the following objectives:
1- Understand the physiology of parathyroid disease and the molecular basis for it.
2- Be able to identify the different manifestations of hyperparathyroidism: Typical, Normocalcemic Hyperparathyroidism, and Normohormonal Hyperparathyroidism.
3- Understand the reasoning for the latest recommendations for treatment of disease.
For more information about hyperparathyroid disease and surgery please visit www.ParathyroidMD.com or call 310-461-0300.
John Ryals- Impacto de las ciencias ómicas en la medicina, nutrición y biotec...Fundación Ramón Areces
El 29 de marzo de 2016 celebramos un Simposio Internacional sobre el 'Impacto de las ciencias ómicas en la medicina, nutrición y biotecnología'. Organizado por la Fundación Ramón Areces en colaboración con la Real Academia Nacional de Medicina y BioEuroLatina, abordó cómo un mejor conocimiento del genoma humano está permitiendo notables avances hacia una medicina de precisión.
Rare Disease Day 2017 March 30 - 31, 2017 Day 2: Genomics for Rare Diseases Dr. Anna Lehman Provincial Medical Genetics Program Adult Metabolic Diseases Clinic Department of Medical Genetics BC Children’s Hospital Research Institute
The connection between genetics and kidney disease lies in the role of inherited genetic factors that can increase the risk of developing various kidney diseases.
Certain kidney diseases, such as Polycystic Kidney Disease (PKD) and Alport Syndrome, have a clear genetic component where mutations in specific genes contribute to the development of these conditions.
Understanding these genetic basis is vital for assessing the risk of kidney disease in individuals with family history and for advancing personalized medicine approaches in prevention, diagnosis and treatment.
Genetic testing plays a significant role in identifying these predispositions and guiding healthcare strategies.
This presentation covers the topic of Malignant bone tumors in brief.
the tumors described here are
1. Osteosarcoma
2. Ewing's Sarcoma
3. Chondrosarcoma
4. Multiple myeloma
5. Chordoma
This presentation will be useful for MBBS, BHMS and BAMS students for exam preparation as well as general understanding of the topic.
Kindly read it in combination with Benign Bone tumors ppt (nutshell) for a better understanding.
In case of any doubts or suggestions, please contact me on WhatsApp (9409012212) or email (dr.aakashnandu@gmail.com)
-Dr Aakash Nandu
Consultant Orthopedic Surgeon
Smit Hospital
Anand, Gujarat
amilial hematuria is a group of inherited glomeular disease that presented with persistant hematuria from childhood. The most frequent cause is thin based membrane disease (COL4A3 or COL4A4 gene mutation). Alport syndrome has a range of presentation of hematuria, proteinuria, sensorineural hearing loss and end stage renal disease depends on the pattern of inheritance of x-linked recessive, autosomal dominant or recessive (mutation COL4A5). Besides that, a syndromic form of AD hematuria with cataract, marcorthrombocytopenia, sensory hearing loss, and nephropathy with the risk of ESRD in early adulthood (mutation MYH9).
There is no curative treatment for Alport syndrome, RAAS inhibition early of childhood has shown significantly slow the progression of chronic kidney disease. Several novel medication improved renal outcome on animals but have not been tested in human.
The other causes of FH are IgA nephropathy, C3 glomerulopathy including (Dense disease, C3 glomerulonephrtis, complement factor H related 5 (CFHR5) nephropathy) ( mutation in genes proteins that regulate alternative complement pathway). There are some case series illustrate the efficacy of eculizumab in native C3 glomeulopathy. Glomerulopathy with fibronectin deposits is another cause of FH (mutation FN1, inherited AD) with no definitive cure.
Familial Mediterenian Fever is another hereditary disease that might present with recurrent microscopic or gross hematuria (mutation M694V). Colchicn and some biological agents was suggested as therapy. Amyloidosis and end stage renal disease occur in follow up.
Similar to 6-3. Dent's disease. Larisa Prikhodina (eng) (20)
Всемирный день почки 2016 в НИКИ им. академика Ю.Е. ВельтищеваKidneyOrgRu
9 марта 2016 г в конференц-зале Научно-Исследовательского Клинического Института имени академика Ю.Е. Вельтищева проведено праздничное мероприятие, посвященное Всемирному Дню Почки, который отмечается во всем мире с 2006 года по инициативе Международного Общества Нефрологов (http://www.worldkidneyday.org). Впервые в этом году Всемирный День Почки был посвящен детям с акцентом на ранней профилактике развития заболеваний почек.
Сотрудники отделения наследственных и приобретенных болезней почек представили для детей презентации об истории проведения праздника, распространенности заболеваний почек с рекомендациями здорового образа жизни для сохранения функций почек.
Было организовано праздничное веселое интерактивное представление для детей с участием Центра детского и юношеского творчества "Бибирево", театра-студии «Рампа», танцевально-акробатических студий «Овация» и «Альфа». Все дети получили праздничные подарки с символом Всемирного Дня Почки.
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
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- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
1. Dent’s disease:
genetics, diagnosis, treatment
Larisa Prikhodina
Department of Inherited & Acquired Kidney Diseases,
Research Institute of Pediatrics & Children’ Surgery,
Moscow, Russia
The IPNA/ESPN Teaching Course
“Pediatric Nephrology: evidence-based statements
and open questions“
Moscow, Russia
October 22-24, 2013
2. Clinical case
History:
• Since age of 10 mo: proteinuria isolated without NS: 0.5-1.4-3.5 g/L
• 1 and 4 y. (locally): steroids 2 mg/kg/d – no effect; Dx: SRNS
• 8 y.: CsA 5 mg/kg/d + steroids 1 mg/kg/d for 10 mo – no effect, serum Cr +50%
Age on admission: 9 y.o.
• Short stature: height: <5‰, weight: 25‰
• Proteinuria isolated: 0.5 g/24h
• Hypercalciuria: Ca/Cr 0.7-1.5
• eGFR: 83.6 ml/min/1.73m2
• Renal biopsy: FSGS
• Steroids & CsA withdrawal
• ACE inhibitors 0.1 mg/kg per day
• Hypothiazide 1-1.5 mg/kg per day
5. Dent’s disease: definition
1964 - Dent C.E. & Friedman M. first report of the disease
1994 - Wrong O.M. coined the term “Dent’s disease”
for the combination of X-linked LMW proteinuria, hypercalciuria,
nephrocalcinosis and/or nephrolithiasis, progressive CRF
Dent disease 1 (MIM: #300009): CLCN5 gene
• X-linked nephrolithiasis with renal failure (MIM: #310468)
• X-linked recessive hypercalciuric hypophosphataemic rickets (MIM: #300554)
• LMW proteinuria with hypercalciuria and nephrocalcinosis (MIM: #308990)
Dent disease 2 (MIM: #300555): OCRL gene
• Clinical phenotype oculo-cerebrorenal syndrome of Lowe
Dent C.E, Friedman M. Arch.Dis.Childh. 39:240-249, 1964;
Wrong O.M. et al. Q.J.Med. 87:473-493, 1994
6. Dent’s disease: epidemiology
• Exact prevalence is unknown (rare CKD)
• 250 affected families reported to date
ICD-10: N39.8 - Other specified disorders of urinary system
Old ERA-EDTA PRD code: 99 - Other identified renal disorders
New ERA-EDTA PRD code: 2929
SNOMED CT concept identifier and fully specified name: 444645005
Familial / hereditary nephropathies: 10201
Wu F. et al. Nephron Physiol 2009; 112:53-62
Shrimpton AE. et al. Nephron Physiol 2009;112:27-36
http://www.era-edta-reg.org
7. Dent’s disease 1: characteristics in males
Major features
Definitions
Affected males
with CLCN5
mutations
LMW proteinuria
(M< 30 kDa)
≥5-x increasing of urinary RBP, β2- or α1
microglobulins
Hematuria
Presence of ≥5 RBC phpf
94%
Hypercalciuria
Urinary Ca excretion >4mg/kg/24h or >age-matched N
89%
Nephrocalcinosis
Renal US
76%
Aminoaciduria
urinary levels of amino acids
100%
44%
Nephrolithiasis
Renal US
42%
Chronic renal failure
ESRD by age 30-50 y.o.
42%
Hypophosphatemia
Serum P <N level and tubular reapbsorption <85%
32%
Rickets
Rachitic changes in bone X-ray
32%
Glycosuria
≥2 episodes of ≥(+) glycosuria without
hyperglycemia
19%
Cho HY. Pediatr Nephrol 2008; 23:243-249;
Claverie-Martin F. Pediatr Nephrol 2011; 26:693-704
8. Dent’s disease 1: renal biopsy findings
No indications for kidney biopsy in pts with phenotype of Dent’s disease!
a. Two glomeruli are globally
sclerotic.
b. Normocellular glomeruli without
segmental sclerosis or podocyte
hypertrophy.
c.
Many collecting ducts are
distended by casts composed of
Tamm-Horsfall protein admixed
with calcifications.
d. Von Kossa stain is positive in the
distribution of the calcifications,
composed of calcium phosphate.
Hodgin JB. Kidney Int 2008; 73:1320-1323
9. Dent’s disease 1: characteristics in females
Females - obligate carriers with milder phenotype:
• Low-molecular-weight proteinuria: 60-90%
• Hypercalciuria: 30%
• Nephrocalcinosis - rare
• ESRD - rare
Sсheinman SJ. Kiney Int 1998; 53:3-17
Ludwig M. et al. Pediatr Nephrol 2006; 21:1241-1250
Copelovitch L. et al. Clin J Am Soc Nephrol 2007; 2:914-918
10. Dent’s disease 2 vs 1: characteristics in males
Major
features
Dent 2
(OCRL1)
Dent 1
(CLCN5)
LMW proteinuria
100%
100%
Hypercalciuria
86%
90%
Nephrocalcinosis
39%
75%
Aminoaciduria
52%
41%
Chronic renal failure
32%
30%
Phosphate wasting
24%
22%
Glycosuria
11%
17%
frequently
rare
Elevated serum levels of muscle
enzymes (LDH, CPK)
Bokenkamp A. J Pediatr 2009; 155:94-99; Bokenhauer D. Pediatr Genetics 2011;
13. Dent’s disease 1: genetics
•
Gene: CLCN5, 17 exons, 170 kb
Nonsense
• Cytogenetic location: Xp11.22
3%
• Protein: CIS-5
• Mutations: >150
5%
3%
1% 1%
2% 1%
Missense
1%
Frameshift deletions
Frameshift insertions
36%
14%
• 10% of the mutations de novo
Donor splice site
Acceptor splice site
Intragenic deletions
33%
Novel splice site
Complete deletions
In-frame insertions
In-frame deletions
• No evidence for major mutational hot spots
• No genotype-phenotype correlation
• No correlations between the presence or absence of mutations and phenotypes
Hoopes RR. et al. Am J Hum Genet 2005; 76: 260-267
14. Dent’s disease 2: genetics
• Gene: OCRL1 (Oculocerebrorenal syndrome of Lowe), 24 exons, 52 kb
• Cytogenetic location: Xq25
• Enzyme: phosphatidylinositol 4,5-biphosphate 5-phosphatase (Golgi apparatus)
• Mutations: >20 (n=44)
All frame shift & splice OCRL1 mutations:
• Dent’s disease 2: cluster in exons 1-7
• Lowe syndrome: affect exons 8-23
OCRL1 mutations:
• in Dent disease 2 not overlap with those causing Lowe syndrome
• p.Ile274Thr, p.Arg318Cys each causing both phenotypes in the same family
Hichri H. et al. Hum Mut 2011; 32: 379-388
15. Dent’s disease neither 1 nor 2: genetics
Candidate genes:
• CLCN4, located on Xp22.3, encoding CIS-4
• CFL1, located on 11q13.1, encoding cofilin
• SLC9A6, located on Xq26.3, encoding Na+/H+ exchanger
No defects
observed
• TMEM27, located on Xp22.2, encoding collectrin
A further candidate gene awaits identification...
Ludwig M. Am J Med Genet 2004; 128:434-435;
Hoopes R.R. Am J Hum Genet 2005; 76: 260-267;
Tosseto E. Pediatr Nephrol 2009; 24:1967-1973;
Wu F. Nephron Physiol 2009; 112:53-62.
16. Dent’s disease 1: pathophysiology
Devust O., Pirson Y. Kidney Int 2007; 72;1065-1072
17. Dent’s disease 1: pathophysiology
9000x
40000x
A. Small vesicles in the secondary foot processes of podocytes.
B-C. Particles in podocytes
40000x
20. Dent’s disease: diagnostic algorithm
(> 100 mg per day)
Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942
21. Dent’s disease: diagnostic algorithm
(> 100 mg per day)
Edvardsson VO. et al. Pediatr Nephrol 2013; 10: 1923-1942
22. Dent’s disease: supportive treatment
Prevention of renal stone formation:
• No special dietary interventions
• High fluid intake
• Oral citrate
• Thiazides: risk of hypovolemia & hypokalemia
Cebotary V. Am J Kidney 2005; 68:642-652
23. Dent’s disease: supportive treatment
Treatment of rickets:
• Vitamin D: doses -?
• Phosphate supplementation: doses -?
Risk of enhance hypercalciuria
& nephrocalcinosis
Slowing down the deterioration of renal function:
• High citrate diet delayed loss of kidney function in a mouse model,
no data in patients
• ACE inhibitors might be potential benefit by reducing proteinuria,
unknown effect on disease progression
Blanchard A. et al. Am J Kidney Dis 2008; 52:1084-1095
24. Dent’s disease: prognosis
Kidney function:
• Normal during childhood
• ESRD in affected males : 30-80% in the 3rd to 5th decade
• ESRD in carrier females: 1 of 10
Renal transplantation:
• Most of patients with ESRD have kidney Tx with good success.
Wrong O.M. et al. Q.J.Med. 87:473-493, 1994;
Bokenkamp A. J Pediatr 2009; 155:94-99.
25. Dent’s disease: conclusion
Evidence-based statements: no
Open questions:
• How the mutations in Dent 1 (CLCN5) and Dent 2 (OCRL) produce a
similar renal phenotype?
• Gene (s): Dent disease neither 1 nor 2?
• Genotype-phenotype correlations?
• Mechanism of hypercalciuria?
• What percentage of FSGS pts might have unrecognized Dent disease?
• What role of glomerular disfunction might play in the loss of renal
function?
26. Dent’s disease: conclusion
• Keeping balance between potential benefit and harm to avoid withheld effective
treatments or administering unnecessary treatments.
• Using of ‘expert groups’ with methodologists to balance personal experience and
available evidence.
Further joint long-term clinical and genetic studies are needed.